Stereoselective alkylation of chiral amines with an alkylating compound is an important reaction in organic synthesis. Generally, a suitable leaving group is placed on the alkylating compound which is then reacted with the chiral amine in the presence of a base. The base absorbs the by-product acid. Suitable leaving groups include moieties such as halide, mesylate, tosylate and the like. Typically, the base used is an organic base such as a tertiary amine. Examples of suitable organic bases are pyridine, triethylamine, N,N-diisopropylethylamine, 2,2,6,6-tetramethylpiperidine (“TMP”) and the like. Thus, for example, J. Tagat et al, Bioorg. Med. Chem., (2001) 11 2143-2146 describe the synthesis shown in Scheme 1, where TMP is used as the organic base in the alkylation reaction:

U.S. patent application Ser. No. 09/562,814, filed May 1, 2000, incorporated herein by reference (now U.S. Pat. No. 6,391,865), discloses the following reaction to prepare the compound of Formula VI. The compound of Formula VI is an intermediate in the synthesis of the compound of Formula VII which is also described in the above-noted
'814 patent application. The '814 patent application discloses the compound of Formula VII as an antagonist of the CCR5 receptor. Antagonists of the CCR5 receptor are known to be useful in the treatment of AIDS and related HIV infections. CCR-5 receptors have also been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. In view of the importance of antagonists of the CCR5 receptor, improved methods of making such antagonists and/or their intermediates are always of interest.
There are two important criteria in stereoselective alkylation of amines. It is important to obtain high yields of the desired product and it is important to produce the product in high chiral purity. Thus, for example, in the reaction depicted in Scheme 1, there are two chiral centers in the starting materials, with R and S configuration respectively. One would ideally like to obtain a high yield of the product compound of Formula III but also prefer to obtain the (S,S) in the product (in that particular reaction) to the highest extent possible. (One chiral center undergoes inversion during the reaction as indicated.) This can also be stated as high stereoselectivity or high selectivity ratio in the reaction. In reactions where an organic base is employed as the catalyst such as those described above in Scheme 1, yields of about 50-65% of the product is obtained with a selectivity ratio of 3:1 of the desired (S,S) isomer to the undesired (R,S) isomer. This necessitates further separation steps, adding to the cost. It will be desirable to obtain a higher selectivity of the desired isomer, preferably also in higher yields, with minimal additional processing steps where necessary.